The annual incidence of medial collateral ligament (MCL) injuries in the U.S. is estimated to be greater than 60,000, one-third of which have concomitant anterior cruciate ligament (ACL) injuries. Clinically, the injured MCL can heal without operative intervention; however, animal studies have shown that the quality of the healed tissue does not return to pre-injury levels, even after one year. There are concerns that suboptimal healing, especially of combined MCL+ACL injuries, can lead to knee disability. Although many treatment methods have been recommended, there is no consensus of opinion regarding the therapeutic approach to MCL+ACL ligament injuries. Thus, the objective of this study is to systematically identify methods for improving the healing of the injured MCL with growth factors. Four specific aims are proposed: 1) EGF, PDGF-BB, betaFGF and TGF-beta1 will be applied to goat MCL fibroblasts and then isolated MCL injuries to identify the best growth factor and optimal dose. 2) The effects of the optimal growth factor treatment on MCL healing will then be explored in a combined- MCL+ACL injury with ACL reconstruction. 3) Gene transfer technology, which allows repeated percutaneous delivery of growth factors to the injury site, will be explored. 4) The combined MCL+ACL injury with ACL reconstruction will be used to study the effects of growth factors on MCL healing and remodeling up to 2 years post-injury. Using an interdisciplinary approach, the morphological, biochemical, and biomechanical properties of MCL healing will be evaluated and correlated. Morphological analyses will consist of gross, histological, and ultra examination. Biomechanical evaluation will consist of measurements of joint instability as well as tensile and viscoelastic behaviors. Biochemical evaluation will involve the quantification and classification of proteoglycans and the determination of content, typing and cross-linking of collagen. Based on published and ongoing studies, growth factors will aid MCL healing and remodeling, while gene transfer technology offers an exciting opportunity for repeated percutaneous delivery of growth factors. The knowledge gained from this study will increase our understanding of the mechanisms of MCL healing, which could be applied to other ligaments.